Active ingredients in marijuana found to spread and prolong pain

August 13, 2009

Imagine that you're working on your back porch, hammering in a nail. Suddenly you slip and hit your thumb instead — hard. The pain is incredibly intense, but it only lasts a moment. After a few seconds (and a few unprintable words) you're ready to start hammering again.

How can such severe pain vanish so quickly? And why is it that other kinds of equally terrible pain refuse to go away, and instead torment their victims for years?

University of Texas Medical Branch at Galveston researchers think they've found at least part of the answer—and believe it or not, it's in a group of compounds that includes the active ingredients in marijuana, the cannabinoids. Interestingly enough, given recent interest in the medical use of marijuana for pain relief, experiments with rodents and humans described in a paper published in the current issue of Science suggest these "endocannabinoids," which are made within the human body, can actually amplify and prolong pain rather than damping it down.

"In the spinal cord there's a balance of systems that control what information, including information about pain, is transmitted to the brain," said UTMB professor Volker Neugebauer, one of the authors of the Science article, along with UTMB senior research scientist Guangchen Ji and collaborators from Switzerland, Hungary, Japan, Germany, France and Venezuela. "Excitatory systems act like a car's accelerator, and inhibitory ones act like the brakes. What we found is that in the spinal cord endocannabinoids can disable the brakes."

To get to this conclusion, the researchers began by studying what happened when they applied a biochemical mimic of an endocannabinoid to inhibitory neurons (the brakes, in Neugebauer's analogy) on slices of mouse spinal cord. Electrical signals that would ordinarily have elicited an inhibitory response were ignored. They then repeated the procedure using slices of spinal cord from mice genetically engineered to lack receptors where the endocannabinoid molecules could dock, and found that in that case, the "brakes" worked. Finally, using electron microscopy, they confirmed that the receptors were in fact on inhibitory, not excitatory neurons. Endocannabinoids docking with them would suppress the inhibitor neurons, and leave pain signals with a straight shot to the brain.

"The next step was to make the leap from spinal slices to test whether this really had anything to do with pain," Neugebauer said. Using anesthetized rats, he recorded the spinal cord electrical activity produced by an injection in the hindpaw of capsaicin- a chemical found in hot peppers that produces a level of pain he compared to a severe toothache. Although the rats were unconscious, pain impulses could be detected racing up their spinal cords. What's more, formerly benign stimuli now generated a significant pain response — a response that stopped when the rats were treated with an endocannabinoid receptor blocker.

"Why was this non-painful information now gaining access to the spinal "pain" neurons?" Neugebauer said. "The capsaicin produced an overstimulation that led to the peripheral nerves releasing endocannabinoids, which activated receptors that shut down the inhibitor neurons, leaving the gates wide open."

Finally, the researchers recruited human volunteers to determine whether a compound that blocked endocannabinoid receptors would have an effect on the increased sensitivity to pain (hyperalgesia) and tendency for normally non-painful stimuli to induce pain (allodynia) often reported in areas of the body near where acute pain had been inflicted. In this case, the researchers induced pain by passing electricity through the volunteers' left forearms, with the intensity of the current set by each volunteer to a 6 on a scale of 1 to 10. At a second session a month later, the volunteers who had received the receptor blocker showed no reduction in perceived acute pain, but had significantly less hyperalgesia and allodynia — a result that matched up well with the endocannabinoid hypothesis.

"To sum up, we've discovered a novel mechanism that can transform transient normal pain into persistent chronic pain," Neugebauer said. "Persistent pain is notoriously difficult to treat, and this study offers insight into new mechanisms and possibly a new target in the spinal cord."

It also raises questions about the efficacy of marijuana in relieving acute pain, given that endocannabinoids and the cannabinoids found in marijuana are so biochemically similar. "If you had a toothache, you probably wouldn't want to treat it with marijuana, because you could actually make it worse," Neugebauer said. "Now, for more pathological conditions like neuropathic pain, where the problem is a dysfunction within the nerves themselves and a subsequent disturbance throughout the nervous system that's not confined to the pain system, marijuana may be beneficial. There are studies that seem to show that. But our model shows cannabinoids over-activating the pain system, and it just doesn't seem like a good idea to further increase this effect."

Related Stories

Neuropathic pain is caused by injury to the peripheral nerves in diseases such as HIV/AIDS, shingles, and cancer or in repetitive motion disorders and trauma, and does not respond well to conventional pain-relieving drugs.

Our bodies sense painful stimuli through certain receptors located in the skin, in joints and many internal organs. Specialized nerve fibers relay these signals coming from the periphery to the brain, where pain becomes conscious. ...

Researchers in the Department of Medicine and Department of Neurosciences at Mount Sinai School of Medicine have discovered that chronic pain can be successfully treated with novel targeted gene therapy. In an effort to find ...

Scientists have long known that the nervous system receptor known as TRPV1 can affect sensations of pain in the body. Now a group of Brown University scientists has found that these receptors – a darling of drug developers ...

Capsaicin, the active ingredient in chili peppers, is most often experienced as an irritant, but it may also be used to reduce pain. A new work published by Drs. Feng Qin and Jing Yao in this week's PLoS Biology uses capsaicin ...

Recommended for you

A biomedical breakthrough published today in the journal Nature reveals never-before-seen details of the human body's cellular switchboard that regulates sensory and hormonal responses. The work is based on an X-ray laser ...

(PhysOrg.com) -- The ability to remember the past and imagine the future can significantly affect a person's decisions in life. Scientists refer to the brains ability to think about the past, present, and future as ...

(PhysOrg.com) -- By implanting an electrode into the brain of a person with locked-in syndrome, scientists have demonstrated how to wirelessly transmit neural signals to a speech synthesizer. The "thought-to-speech" process ...

(PhysOrg.com) -- Most people can easily tell the difference between reality and fantasy. We know that characters in novels and movies are fictitious, and we also understand that historical figures - even if we’ve never ...

(PhysOrg.com) -- Humans don’t always make the most rational decisions. As studies have shown, even when logic and reasoning point in one direction, sometimes we chose the opposite route, motivated by personal bias or simply ...

24 comments

I question the controls this study used in addition to the vague definition used in this article. In the field of chemical substances, there are multiple cannabioids, several of which the body produces for very different functions. Cannabinoids of all types have been found to perform inhibitor functions as well as excitation functions based soley on the shape on content of the substance. Marijuana when smoked or ingested releases large amounts of two cannabinoids, which of the two was the subject of this study, or was it one of the many trace cannabinoids also produced by marijuana smoke?

Once again, the title of this article is misleading... The researchers synthesized a chemical "like" what is found in marijuana, as opposed to actually using the cannabinoids from marijuana.

given that endocannabinoids and the cannabinoids found in marijuana are so biochemically similar.

Similar, but not the same. I'd like to see a study done that actually uses cannabis instead of something that is "mostly like" cannabis. Additionally, they only looked at the effects on the spinal nerves, as opposed to a bigger picture of the interactions in the brain that cannabinoids trigger. Completely anecdotal: it seems that cannabis creates a sensation of "forgetfulness" or lack of care about pain as opposed to actually blocking the pain itself.

...hammering in a nail. Suddenly you slip and hit your thumb instead %u2014 hard. The pain is incredibly intense...

Yeah but, if you're stoned you can't stop laughing about it because you think it's incredibly funny, then you forget what you were doing and go inside and eat 4 or 5 snickers bars. Distraction can equal sessation, as with dental drills and music. Just so your dentist isn't stoned at the time.

"If you had a toothache, you probably wouldn't want to treat it with marijuana, because you could actually make it worse,"

Experience tells me this is not accurate because sitting there sober with a toothache vs stoned with a toothache anyone willing to be stoned would tell you their choice (its not like any toothache isn't already hurting before you've smoked, and after you can at least relax a little). Plus these studies where they try and figure out marijuana is bad without actually using it are more designed to make it look as though marijuana is so dangerous it can't even be studied directly, yet opiates and cocaine derivatives are available at any pharmacy across the world with a prescription. Its available in California basically and if you really want to do actual science with real data there are ways to make a real study happen. To play with other models vs the real thing at this point is like observing the milky way exclusively through binoculars while the Hubble's in orbit over your head, hardly advancing any science.

I don't see any comments in the article that they actually tried it for themselves. It cracks me up how all these people who do these 'studies' have never even taken a whiff of marijuana. It helps alleviate my pain from gout and other minor aches and pains. Why would millions of people use medicinal marijuana if it made pain worse? HELLLLLOOOOO? What planet are u from?

It may well be true, in its own limited context, however,
I found it to be misleading, and to perhaps contradict a
lot of personal testimony of people with those kinds of
chronic "neuropathic pain" who say that they benefited.

This study admits that kind of chronic pain
might well be treated by medical marijuana.

However, like most other sensationalized
anti-pot propaganda, the report tended to
be presented to cast bad aspersion on pot.

In the end, this study seems to me to merely be another
confirmation of general effects of getting high, that when
you get high, both the good and the bad experiences
tend to be amplified, so that food tastes better, and
music sounds better, and so on and so forth, and so,
it would seem to make also make good sense that if
"you hit your thumb with a hammer," then it would
tend to hurt worse when you were high, than if
you were not high when you hit your thumb ...

Life is generally a package deal,
& the good comes with the bad.

The price of getting high may well be
that good sex is better, however, the
bad sex ends up being worse, etc. ...

When I'm smoking weed, I don't try to hammer a nail, in the first place. These articles about a cannabis are becoming more and more pathetic. Anyway, I think those scientists are just covering for getting high at work. "We had to test it and it was really bad, Mr. Republican, who ordered and is paying for this study."

This is a very interesting and promising study which may help devising better pain relief medications, even though it's packed up with the usual appalling anti marijuana hype.

Personally I would not attempt treating pain with marijuana because in my case it greatly enhances every sensation and I would expect the pain to get worse (though I admit my expectation may be wrong here it is enough to stop me from even trying).
There is however plenty of evidence that it does help people with chronic pain.

One possible explanation is that cannabinoids present in marijuana compete with endocannabinoids for those same receptors but due to chemical differences do not work as well in shutting down inhibitory neurons. This way a person whose spinal cord already produces endocannabinoids may experience some pain relief due to plant cannabinoids preventing natural cannabinoids from exerting their full effect and completely blocking inhibitory neurons. In other words marijuana endocannabinoids may only "half-block" the inhibitory neurons. If your inhibitory neurons were not blocked before you would experience increase in pain, if they were already blocked completely you would experience pain relief.

This is just one possible mechanisms but there are many other possibilities, for example overstimulation with cannabinoids may activate some sort of negative feedback mechanism which downregulates receptors for example by degrading them. Finally the pain relief effects may stem from some other part of the nervous system.

I would agree with this article in a slight way. As an avid smoker, I do notice back, shoulder, and neck pain that I chronically have to dicipate with marijuana use, however; while under the influence of THC, if I strike a finger with a hammer, I do notice myself being distraught by the pain for some time after the initial strike.
All in all, I think the article is incredibly misleading as THC is the active ingredient in marijuana, however it is not the be all - end all of cannibinoids.

So I'm out there one day being a busy little Canadian beaver with chopping my firewood and all, just like Shatner in that Trek movie, and I've run up against one of those more difficult chunks with the knots so of course I've grabbed a wedge and I'm driving it in with the back-end of the axe and the axe misses (because axes don't really make all that good of a hammer anyhow) and just about takes one of my fingers off. I turn blue, the air around me turns blue, and the two Jehovah's Witnesses who happened to be passing by at the time turn blue with grave concern regarding the blueness that I'm inflicting upon the surrounding atmosphere - it's basically an environmental disaster. I manage to convince them in short order that I really do NOT wish to live 'forever', and then I retreat back into my cabin to wrap my finger up so I don't bleed all over the bloody place and also to smoke a particularly large bowl (being VERY thankful to have a pipe on hand at that particular moment!) so I could forget all about the nasty incident for the while. That worked fine, so I continued on with my fetching-water-from-the-creek and recharging-the-cabin's-batteries chores and all went well until the next morning when I had to go to work and _couldn't_ smoke anymore - *that's* when the pain really began to kick in, and that whole day was utterly miserable until I finally got back home for the evening and smoked another few bowls.

Then there was the time I pranged up my hang-glider, and broke my leg as a result... triple-compound fracture, and the mediquacks that shoved a rod into it and patched it all up were all saying that it'd be a good half-year at least before I'd be walking normally again - so; I got hauled back home to my cabin, and then immediately stocked up on several more bags of cannabis so I could stay stoked-up on a more-or-less continual basis... and after five weeks I was walking perfectly well again, without crutches. No undue pain, and back to work as normal - thus making my employer less nervous about shift coverage.

And the moral of this story is: umm... errr... ahh; I forgot. Make up one yourself then, if you really need such - I'm going to go roll a joint now.

I guess I've just been imagining the relief of my arthritic back pain provided by marijuana all these years... Guess I should better hop back on the 'big pharma approved' pain meds and tell the doc to start monitoring my liver for signs of organ failure again... or not.

Ill gladly volunteer myself to smoke ganja :) and proof this article wrong. Like many other substances people react differently marijuana so what might work for one person might not necessarily work for another.

It is the new kinder, gentler war on drugs. Propaganda is preferable to hard time, doncha think? Since the USA can no longer afford to incarcerate hundreds of thousands of non-criminals, look for more misleading information in tandem with decreased enforcement. Is this progress?

Please sign in to add a comment.
Registration is free, and takes less than a minute.
Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.